A strong need exists to provide compositions, pharmaceuticals and/or medicaments with anti-proliferative activity. Such compositions, pharmaceuticals and/or medicaments may posses not only strong activity, but also exert diminished side effects in comparison to other anti-proliferative agents. Furthermore, the spectrum of tumors responsive to treatment with such compositions, pharmaceuticals and/or medicaments may be broad. Active ingredients of this type may be suitable in the mentioned indication as single agent, and/or in combination therapy, be it in connection with other therapeutic agents, with radiation, with operative/surgical procedures, heat treatment or any other treatment known in the mentioned indications.
One or more of such objectives is achieved, or other advantages shown, by making available the compounds of the present invention as defined herein. Compounds of the present invention are derivatives of squaric acid, in particular compounds of the present invention are derivatives of 3,4-diamino-cyclobut-3-ene-1,2-dione.
The compounds of the present invention can be suitable for further pre-clinical or clinical research and development towards the treatment of a variety of diseases including cancer, proliferative, degenerative and other diseases. The further development of such new therapeutic opportunities provided by the present invention would result in one or more effective therapies, and marketed drugs, for particularly debilitating diseases including those diseases and disorders listed herein.
It is known that various derivatives of squaric acid, substituted in a specific manner, have pharmacologically useful properties. In particular, certain derivatives of squaric acid are known to possess anti-proliferative activity. These compounds however are structurally dissimilar from the compounds of the present invention.
Compounds comprising 3,4-diamino-cyclobut-3-ene-1,2-dione moieties have been described as potassium channel openers (J Med Chem (2000) 43, 1187; J Med Chem (2000) 43, 1203; WO 02/062761), as smooth muscle relaxants (WO 96/15103; WO 96/14300; WO 95/14005), as chemokine receptor binders (WO 02/083624) or integrin receptor binders (WO 00/035864; U.S. Pat. No. 6,420,396; U.S. Pat. No. 6,677,360). U.S. Pat. No. 5,532,245 discloses compounds comprising a 3,4-diamino-cyclobut-3-ene-1,2-dione moiety. Clinical use of the compounds of U.S. Pat. No. 5,532,245 is disclosed as being limited to diseases amenable to treatment with smooth muscle relaxants, such as urinary incontinence or irritable bowel syndrome. WO00/35855 discloses compounds comprising a 3,4-diamino-cyclobut-3-ene-1,2-dione moieties for use in the treatment of inflammatory and autoimmune diseases. WO02/076926 discloses compounds comprising a 3,4-diamino-cyclobut-3-ene-1,2-dione moiety for the treatment of cancer. WO02/083624 discloses compounds comprising a 3,4-diamino-cyclobut-3-ene-1,2-dione moiety for the treatment of cancer. WO01/47867, WO02/04426, WO02/10136, and WO02/42264 disclose compounds comprising 3,4-diamino-cyclobut-3-ene-1,2-dione moieties as integrin antagonists. Compounds of these latter applications carry at least two aryl or heteroaryl substitutions on one amino group of the 3,4-diamino-cyclobut-3-ene-1,2-dione moiety and another aryl or heteroaryl substitution on the other amino group of the 3,4-diamino-cyclobut-3-ene-1,2-dione moiety. U.S. Pat. No. 6,677,360 discloses 3,4-diamino-cyclobut-3-ene-1,2-dione moieties as integrin antagonists. Compounds of this application carry at least two phenylene groups arranged in tandem.